A gene is considered a candidate gene for type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. Candidate genes analyzed in the past year include: ENPP1, PTPN1, SIM1, INSIG2, GLP1R, GLP2R, GNAT3, IAPP, IDE, ISL-1, PAX4, PC-1, RBP4, PBEF and TCF7L2. Poymorphisms were identified in all of these genes and analyzed for association with type 2 diabetes, obesity, or metabolic traits that predict these diseases. Varaints in TCF7L2 have been highly associated with type 2 diabetes in multiple populations and this gene appears to be the most highly replicated diabetes suceptiblity gene to date. However, variants in this gene show no associaiton with type 2 diabetes among the Pima Indians of Arizona, suggesting that the etiology of this disease is different in Native Americans as compared to other populations. In contrast, our recent studies of Sim1 suggest that this gene will be our first common susceptibility gene for obesity in the Pima Indians. We initially studied this gene as a candidate for morbid obesity, and identified multiple SNPs that were associated with morbid obesity in a case/control study of 300 obese (mean BMI= 50) and 126 lean (mean BMI=26) Pima subjects. We recently genotyped these variants in a large, unselected sample of Pima Indians (N=3500), and found that common variants (all in high linkage disequilibrium (L.D.) in the Pima Indians, with allele frequency= 0.4) are strongly associated with BMI (p=0.00001, age and sex adjusted) in this general population-based sample. We are currently working to determine the specific functional variant.